Malignancies of B and T lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal lymphoid cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Our studies are directed first at determining how similar the tumors of the two species are so that we can understand how to develop better mouse models for human neoplasms. Relevant models would provide opportunities for understanding the mechanisms driving diseases as well as for developing new approaches to diagnosis, treatment and possibly prevention. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. A second major purpose of our studies then is to determine if and how these mechanisms also contribute to mouse lymphoid cell lineage neoplasms. Finally, we believe the knowing how mutant or abnormally expressed genes contribute to tumorigenesis will direct us to important insights into how they contribute to normal T and B cell biology. These directions have led us to study a spectrum of mice that develop T or B cell lymphomas either spontaneously or following genetic manipulations that silence or aberrantly activate selected genes with much of the work being done in collaborations with scientists at the NIH and in academia.[unreadable] Oncogenic transformation of cells requires several mutations that lead to growth factor sufficiency and independence of growth suppressive effects. In humans, these mutations are often due to recurring chromosomal changes while in mice they are caused most often by mutagenic integrations of retroviral DNA into the genome. Studies of a large number of aging mice predisposed to B cell lymphomas highlighted candidate cancer genes in the Notch and Nf-kB signaling pathways along with genes governing B cell lineage commitment. Indeed, current studies have identified a critical role for Notch signaling in mouse plasma cell tumors, termed plasmacytomas, (PCT), while overexpression in mice of another target, Edg5, resulted in multiple tumors with chromosomal instability. [unreadable] B and T cells differ from all other somatic cells in that they develop physiologic single and double strand breaks (DSB) in DNA in order to generate immune receptors and diversify B cell antigen-binding avidity through somatic hypermutation (SHM) and function by class switch recombination (CSR). Both SHM and CSR are dependent on the activity of a single enzyme, AID (activation-induced cytidine deaminase) in germinal center (GC) B cells. Remarkably, studies of mice predisposed to development of GC-derived B cell lymphomas or PCT showed that AID was critical to the development of both tumor types. Other DSB that occur during early B cell differentiation required repair by interactions of a complex set of proteins. Studies of one of these proteins, ARTEMIS, showed that it is required to suppress tumor development in multiple tissues including tumors of early B lineage cells. Importantly, humans deficient in activity of this protein are also predisposed to developing lymphomas, providing a tractable mouse model for understanding this phenomenon. Together, these observations indicated that physiologic DSB required for normal B cell development inadvertently predispose the same cells to development of lymphomas and leukemias. [unreadable] The initiation and progression of lymphoid tumors is also influenced by chronic extracellular stimuli and the constitutive activation of intracellular signaling pathways that have been thought to synergize with signals driven by engagement of antigen-specific T or B cell receptors. Activated forms of the transcription factor, STAT5, are frequently seen in human lymphomas and mice expressing an activated STAT5b gene develop thymic CD8+ T cell lymphomas indicating that it can function as an oncogene. Remarkably, studies of mice rendered incapable of signaling through the T cell receptor developed accelerated lymphomas indicating that synergy between T cell receptor and STAT5 signaling was not required for disease.